Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat

Anselmi, Laura; Bove, Cecilia; Coleman, F. Holly; Le, Kassel; Subramanian, Megha; Venkiteswaran, Kala; Subramanian, Thyagarajan; Travagli, R. Alberto

doi:10.1038/s41531-018-0066-0

Cited by 45 publications

(47 citation statements)

References 62 publications

(82 reference statements)

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“…They also made a vagotomy, preventing the progression of PD effects and constraining the appearance of pathological α-syn only to enteric neurons. These reports demonstrated that coadministration of these molecules induces a progressive, l-dopa-responsive PD which is preceded by gastric dysmotility (Anselmi et al, 2018). Finally, it is important to notice the role of the microbiota in the CNS, where the host is constantly controlling the maturation and function of the microglial cells (Cosin-Tomas et al, 2018), a reason to consider their effects and imbalances in the subject, which, in the future, could be key in the control, prevention, or even treatment of PD.…”

Section: The Neuroimmune Context Of Pdmentioning

confidence: 98%

Neuroinflammation as a Common Feature of Neurodegenerative Disorders

et al. 2019

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Neurodegenerative diseases share the fact that they derive from altered proteins that undergo an unfolding process followed by formation of β-structures and a pathological tendency to self-aggregate in neuronal cells. This is a characteristic of tau protein in Alzheimer’s disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson’s disease, and huntingtin in Huntington disease. Usually, the self-aggregation products are toxic to these cells, and toxicity spreads all over different brain areas. We have postulated that these protein unfolding events are the molecular alterations that trigger several neurodegenerative disorders. Most interestingly, these events occur as a result of neuroinflammatory cascades involving alterations in the cross-talks between glial cells and neurons as a consequence of the activation of microglia and astrocytes. The model we have hypothesized for Alzheimer’s disease involves damage signals that promote glial activation, followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases. These patterns of pathological events can be applied to several neurodegenerative disorders. In this context, the involvement of innate immunity seems to be a major paradigm in the pathogenesis of these diseases. This is an important element for the search for potential therapeutic approaches for all these brain disorders.

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Section: The Neuroimmune Context Of Pdmentioning

confidence: 98%

Neuroinflammation as a Common Feature of Neurodegenerative Disorders

et al. 2019

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“…In humans, truncal but not selective vagotomy has been suggested to have a protective effect towards Parkinson's disease (Liu et al, 2017;Breen et al, 2019). Furthermore, accumulation of α-synuclein, a hallmark of Parkinson's disease, has been detected in ENs (Anselmi et al, 2018) and vagal nerves have been proposed as the key mediator for α-synuclein transport between the ENs and the brain in mice (Santos et al, 2019). α-synuclein was detected in the DMV and substantia nigra (Kim et al, 2019;Van Den Berge et al, 2019) after injection of pathologic α-synuclein into the muscular layer of the pylorus and duodenum, suggesting gut to brain transport of α-synuclein.…”

Section: Tension Receptorsmentioning

confidence: 99%

Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents

2020

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Gastrointestinal (GI) vagal afferents convey sensory signals from the GI tract to the brain. Numerous subtypes of GI vagal afferent have been identified but their individual roles in gut function and feeding regulation are unclear. In the past decade, technical approaches to selectively target vagal afferent subtypes and to assess their function has significantly progressed. This review examines the classification of GI vagal afferent subtypes and discusses the current available techniques to study vagal afferents. Investigating the distribution of GI vagal afferent subtypes and understanding how to access and modulate individual populations are essential to dissect their fundamental roles in the gut-brain axis.

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“…There is a long tradition of investigation into the etiology and pathogenesis of Parkinson's Disease (PD) that seeks to link molecular (pesticides, oxidative stress, protein dysfunction etc.) (Hwang, 2013; Ortiz et al, 2016; Chiti and Dobson, 2017; Anselmi et al, 2018; Stykel et al, 2018) and subcellular (mitochondrial dysfunction etc.) (Henchcliffe and Beal, 2008; Reeve et al, 2018; Tsai et al, 2018) factors with the disease development.…”

Section: Introductionmentioning

confidence: 99%

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2019

Front. Neural Circuits

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Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in ‘stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.

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Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat

Cited by 45 publications

References 62 publications

Neuroinflammation as a Common Feature of Neurodegenerative Disorders

Neuroinflammation as a Common Feature of Neurodegenerative Disorders

Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity

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